NcXHF

EVOLVING IMMUNOTHERAPY STRATEGIES IN UROTHELIAL CANCER
The median time to fırst response was 42 days, and the median
overall survival times were 4.2 months for the strong
IHC expression group and 2.7 months for the weak IHC expression
group. Importantly, the main toxicity of the therapy
was fatigue, and grade 3 adverse events only occurred in 4%
of patients (no grade 4 or 5 toxicity noted). On the basis of the
encouraging results of this trial, the U.S. Food and Drug Administration
(FDA) granted MPDL3280A a breakthrough
designation in June 2014.
VACCINES
HER2 status has prognostic and therapeutic value in breast
cancer. Recently reported results from The Cancer Genome
Atlas 48 found that HER2 alterations were almost as frequent
in urothelial carcinoma compared to the TCGA breast cancer
study. A meta-analysis of nine retrospective studies (2,242
patients) indicated that HER2 expression signifıcantly correlated
with poorer disease-specifıc survival (hazard ratio [HR]
2; 95% CI, 1.22 to 3.29; p 0.006) and disease-free survival
(HR 1.68; 95% CI, 1.33 to 2.14; p 0.0001) of patients with
bladder cancer. 49 DN24–02 is an investigational active cellular
immunotherapy targeted at the HER2 receptor. It consists
of autologous PBMCs, including APCs, which are activated
ex vivo with a recombinant fusion protein. A randomized
phase II study comparing adjuvant DN24–02 to the standard
of care in patients with high-risk urothelial cell carcinoma
met accrual and results are pending at this time. Colleagues at
the National Institutes of Health Clinical Center are investigating
the use of another HER2/neu vaccine in a phase I trial
(NCT01730118). This trial investigates a novel therapeutic
autologous AdHER2 dendritic cell vaccine in patients with
HER2-expressing metastatic solid tumors as well as in patients
with adjuvant bladder cancer who have HER2-positive
tumors. In preclinical animal models, the vaccine was documented
to eradicate large established tumors through the induction
of polyclonal, anti-HER2 antibodies.
M phase phosphoprotein 1 and disheveled, EGL-10, and
pleckstrin (DEP) domain have roles in the growth of bladder
cancer cells. In addition, human leukocyte antigen (HLA)-
A24–restricted peptide epitopes corresponding to parts of
these two proteins have been identifıed that can induce
peptide-specifıc cytotoxic T cells. Of the six patients with
metastatic bladder cancer enrolled in a phase I trial, four developed
vaccine-specifıc cytotoxic T cells. 50
Cancer testis antigens (CTAs) are a group of tumorassociated
antigens with restricted expression in normal tissues
but with expression in a variety of tumors. Sharma et al 51
examined the expression patterns of nine CTA by IHC and
reverse transcriptase (RT) polymerase chain reaction (PCR)
in a panel of 95 high-grade bladder tumors. They found that
at least one CTA was expressed in 77% of the tumors and that
61% of the tumors expressed more than one. A recombinant
NY-ESO-1 protein vaccine coadministered with GM-CSF
and BCG as immunologic adjuvant was tested in six patients
with organ-confıned disease. 52 NY-ESO-1–specifıc antibody responses
were induced in fıve patients, CD8 T-cell responses occurred
in one patient, and CD4 T-cell responses were seen in all
six patients. A phase II trial (NCT01435356) evaluating the effıcacy
of the recMAGE-A3 vaccine after cystectomy is currently
recruiting; a phase I trial (NCT01498172) evaluating MAGE-A3
plus BCG has just completed, and results are pending.
PANVAC is a poxviral cancer vaccine that has demonstrated
therapeutic effıcacy against a variety of carcinomas.
PANVAC consists of a primary vaccination with a
replication-competent recombinant vaccinia vector followed
by multiple boosts with a replication-incompetent recombinant
fowlpox vector. These vectors contain transgenes for
both human T-cell costimulatory molecules and tumorassociated
antigens against Mucin-1 (MUC-1) 53,54 and carcinoembryonic
antigen (CEA). 55 MUC-1 and CEA are
expressed in approximately 93% and 76% of high-grade bladder
tumors, respectively. A phase II study (NCT02015104)
assessing PANVAC in combination with intravesical BCG in
patients who have experience treatment failure with prior
BCG therapy is recruiting patients at the NCI and the Rutgers
Cancer Institute of New Jersey.
ADOPTIVE T-CELL THERAPY
Adoptive T-cell therapy involves the infusion of externally
manipulated T cells to give rapid immunity instead of relying
on the immune system to generate T cells after being presented
with an antigen. Before infusion, however, patients require
nonmyeloablative leukoreductive therapy using
irradiation and chemotherapy. 56 This area of cancer immunotherapy
began with tumor-infıltrating lymphocytes (TILs).
These TILs are extracted from tumor tissue, expanded ex
vivo, and then reinfused into patients. This approach was applied
recently to patients with metastatic urothelial cancer in
a feasibility study. Tumor lymphocytes were obtained from
lymph nodes draining metastatic tumors; after in vitro culture,
the lymphocytes were reinfused into the patients without
any adverse effects. 57 However, it is unclear how effective
this approach will be. A more novel approach applies extraction
of TILs from tumors and whole-exomic sequencing of
the tumors to identify mutations characteristic of the tumor.
The TILs are probed to see if they recognize any of the mutations;
then, adoptive transfer of the TILs containing
mutation-specifıc polyfunctional T cells is performed. 58 This
technology can be applied to any malignancy, and, given that
urothelial cancer has the third highest rate of mutations, it is
well positioned for this type of therapy. We are assisting our
colleagues who are performing this work at the NCI in the
application of this approach to urothelial tumors.
TIL therapy is limited in that TILs have to be retrieved
through an invasive procedure and require the ability to grow
ex vivo. As a result, genetic modifıcation of the T-cell receptor
(TCR) only requires isolation from peripheral blood, viral
transduction to express a recombinant TCR specifıc for a tumor
antigen, and reinfusion after expansion of these genetically
engineered TCRs. CTAs, as mentioned earlier, are good
candidates for TCR gene therapy, because they are not
present in adult somatic tissues and are found with high
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